Protein Tyrosine Phosphatase 1B Reduction Regulates Adiposity and Expression of Genes Involved in Lipogenesis

Abstract

Protein tyrosine phosphatase 1B (PTP1B) has been implicated as a negative regulator of insulin action. Overexpression of PTP1B protein has been observed in insulin-resistant states associated with obesity. Mice lacking a functional PTP1B gene exhibit increased insulin sensitivity and are resistant to weight gain. To investigate the role of PTP1B in adipose tissue from obese animals, hyperglycemic obese (ob/ob) mice were treated with PTP1B antisense oligonucleotide (ISIS-113715). A significant reduction in adiposity correlated with a decrease of PTP1B protein levels in fat. Antisense treatment also influenced the triglyceride content in adipocytes, correlating with a downregulation of genes encoding proteins involved in lipogenesis, such as sterol regulatory element-binding protein 1 and their downstream targets spot14 and fatty acid synthase, as well as other adipogenic genes, lipoprotein lipase, and peroxisome proliferator-activated receptor ␥. In addition, an increase in insulin receptor substrate-2 protein and a differential regulation of the phosphatidylinositol 3-kinase regulatory subunit (p85␣) isoforms expression were found in fat from antisense-treated animals, although increased insulin sensitivity measured by protein kinase B phosphorylation was not observed. These results demonstrate that PTP1B antisense treatment can modulate fat storage and lipogenesis in adipose tissue and might implicate PTP1B in the enlargement of adipocyte energy stores and development of obesity. Diabetes 51:2405-2411, 2002 P rotein tyrosine phosphatases play an important role in the regulation of insulin signal transduction, and a number of protein tyrosine phosphatases have been reported to regulate insulin receptor (IR) signaling both under normal conditions and in the insulin-resistant state (1-3). PTP1B has been shown to serve as a negative regulator of IR and IR substrate (IRS)-1 phosphorylation (4,5). In addition, several studies have demonstrated that increased expression of PTP1B occurs in insulin-resistant states associated with obesity (6,7). Mice lacking a functional PTP1B gene exhibit increased insulin sensitivity in liver and skeletal muscle but fail to show increased insulin sensitivity in fat. They are resistant to weight gain on a high-fat diet (8) and are reported to have low adiposity due to a marked reduction in fat cell mass without a decrease in adipocyte number (9). The reason for the obesity resistance observed in PTP1BϪ/Ϫ mice is unclear. Increased leptin sensitivity in PTP1BϪ/Ϫ mice has been suggested as a mechanism for increased energy expenditure (9). Although these reports demonstrate a major role of PTP1B in the modulation of insulin sensitivity in liver and muscle, they fail to address the effect of reducing PTP1B expression in adipose tissue in obese diabetic animals.Recently, we have investigated the effects of PTP1B antisense (ISIS-113715) treatment on insulin resistance and the regulation of insulin signaling in ob/ob diabetic mice. Interestingly, hyperglycemic ob/ob mice as well as db/db mice...

Single nucleotide polymorphisms of protein tyrosine phosphatase 1B gene are associated with obesity in morbidly obese French subjects

“…Increasing numbers of concordant studies [18,19,20] in Caucasian populations, including ours, suggest that PTP 1B might contribute to obesity and metabolic syndrome traits. The association between PTP 1B SNP and obesity might be consistent with recent animal studies showing that PTP 1B could contribute to the enlargement of adipocyte stores and to the development of obesity [11,13]. Among the French obese subjects, PTP 1B variants were also associated with obesity-related traits such as dyslipidaemia.…”

“…These PTP 1B-invalidated mice are resistant to weight gain when fed a high-fat diet [11]. Decreased lipogenesis and adiposity were described in obese ob/ob mice treated by PTP 1B antisense oligonucleotide [13]. Lower adiposity in these mice was associated with a down-regulation of sterol regulatory element binding protein 1 (SREBP-1), a transcription factor involved in glycolysis, lipogenesis and adipogenesis [14].…”

Protein Tyrosine Phosphatase 1B Regulates Pyruvate Kinase M2 Tyrosine Phosphorylation

“…Antisense oligonucleotides that lower PTP1B levels only in adipose tissue and liver reduce diet-induced obesity and enhance insulin signaling in obese (ob/ob) and diabetic (db/db) mice (48,49). Similarly, administration of PTP1B antisense oligonucleotides to monkeys reduces PTP1B in adipose tissue and liver and improves insulin sensitivity (50).…”

Protein-tyrosine Phosphatase 1B Deficiency Reduces Insulin Resistance and the Diabetic Phenotype in Mice with Polygenic Insulin Resistance

“…We recently found that deletion of PTP1B selectively in neurons increases insulin sensitivity, but as in total body PTP1B Ϫ/Ϫ mice, adiposity is reduced in neuron-specific PTP1B Ϫ/Ϫ mice (26). Reduction of PTP1B expression primarily in liver and adipose tissue of ob/ob mice by antisense oligonucleotides has also been reported to improve insulin sensitivity, but again, largely in association with decreased adiposity (27)(28)(29). All of these data strongly support a physiological role for PTP1B in negatively regulating insulin signaling in rodents and humans.…”